Diabetes mellitus is a disease in which the body's metabolism of sugars is greatly impaired due to either the faulty secretion of insulin by the pancreas or the body's inability to properly use the insulin. Insulin is a hormone that regulates the level of blood glucose, and controls the rate at which glucose is transported into fat and muscle cells. In addition, insulin regulates numerous anabolic processes in a variety of other cell types. When excess glucose is transported into fat cells it is converted to triglycerides which are stored as energy reserves and, eventually, when the stores are needed and insulin is low, the triglycerides are broken down into fatty acids which are either released or converted by the liver into ketones. Insulin actively inhibits breakdown of triglycerides (lyolysis) in fat cells and actively stimulates synthesis of triglycerides from glucose. Therefore when insulin levels are low, triglycerides are broken down and the stored fat is lost. Insulin also stimulates glucose uptake into muscle cells, where the glucose is consumed to produce energy or is converted into glycogen, which is a storage form of glucose. In the liver, glucose transport is not insulin sensitive but conversion of intracellular glucose to glycogen is stimulated by insulin. The liver can convert amino acids to glucose; this process is inhibited by insulin. Binding of insulin by tissue cells depends on insulin receptors on the surface of insulin-sensitive cells. The receptor/insulin complex which extends across the cell membrane transmits signals to the inside of the cell. These signals increase glucose transport in selected cells and alter cell metabolism in most cells.
Diabetes is characterized by elevated levels of glucose in the blood, which can in turn lead to high glucose levels in the urine. Four types of diabetes mellitus have been clinically observed: non-insulin dependent diabetes mellitus (NIDDM); insulin-dependent diabetes mellitus (IDDM); gestational diabetes mellitus (GDM); and diabetes secondary to other conditions. The total incidence of diabetes in the United States population in 1993 was 3.1%, a 500% increase over the incidence of diabetes in 1958. See M. I. Harris, Classification, Diagnostic Criteria, and Screening for Diabetes, In: Diabetes in America (National Institutes of Health, Second Ed. 1995).
IDDM, GDM and secondary diabetes constitute a small portion of the diabetes problem in the United States. Insulin-dependent diabetes is typically manifest as a lack of physiologically functional insulin. IDDM cases typically occur at an early age as a result of autoimmune destruction of the pancreatic .beta.-cells, which are responsible for insulin production. IDDM can also result from cytotoxic destruction of the pancreas, or from errors in insulin synthesis and processing. The most debilitating of diabetic conditions, IDDM fortunately only constitutes approximately 5% of known cases in the United States. Gestational diabetes mellitus is observed in 3%-5% of all pregnancies and typically disappears postpartum. GDM is usually manageable through dietary alterations alone. Diabetes secondary to other conditions (such as sepsis) represents a minor component (1%-2%) of the total cases encountered, but can be serious since it manifests in individuals whose health is already compromised.
The vast majority of diabetics are diagnosed with NIDDM, also commonly referred to as "type II" or "adult-onset" diabetes. In the United States, the incidence of NIDDM is rising sharply. Of the 7.8 million people characterized as diabetic in the United States in 1993, 90%-95% were considered to be non-insulin dependent diabetics. According to the National Institutes of Health, the prevalence of NIDDM in the United States population was 6.2% of people 45-64 years of age, and 10.4% of people greater than age 64. However, independent public health surveys indicate that these numbers are greatly underestimated. In addition, impaired glucose tolerance, an intermediate state between normal and diabetic, is manifest in 42% of people ages 65-74.
The etiology of NIDDM is heterologous. Several genetic syndromes have been associated with the disease. Usually NIDDM is associated with hyperinsulinemia, or excess insulin, rather than a deficiency of insulin. Insulin receptors do not respond to normal levels of insulin, thereby requiring the pancreas to produce greater quantities of insulin. Eventually the pancreas is unable to meet the demand for insulin. Risk factors for NIDDM include older age, family history of diabetes, minority ethnicity, and obesity. Intraabdominal obesity, long duration of obesity, physical inactivity, and morbid obesity, in particular, predispose one to NIDDM.
Chronic hyperglycemia and hyperinsulinemia observed in NIDDM are associated with a large number of health complications. In 1986, NIDDM-related deaths accounted for approximately 17% of all deaths in the United States for people over age twenty-five. In particular, cardiovascular disease secondary to NIDDM was responsible for over half of these deaths.
The complications that arise due to diabetes adversely affect the quality of life of those who suffer from it and result in significant health care costs. General disability affects over 50% of diabetics. Health care services are provided to diabetics with much greater frequency than to age-matched non-diabetics. Vision disorders, especially diabetic retinopathy, afflict over 20% of NIDDM patients. Some form of neuropathy, kidney disease, vascular disease, or cardiovascular disease eventually affects nearly all diabetics. Diabetes patients comprise 35% of all new cases of end stage renal disease. The annual cost of treating diabetes-associated renal disease in the United States exceeds two billion dollars.
Adenosine is an extracellular messenger generated by all cells in the body. Adenosine, substances that mimic the actions of adenosine, and substances that antagonize the actions of adenosine have important clinical applications. Adenosine regulates a wide array of physiological functions, but its effect in any given cell depends on the type or subtype of adenosine receptor expressed on the surface of that cell.
The effects of adenosine are mediated by four adenosine receptor subtypes, A.sub.1, A.sub.2A, A.sub.2B, and A.sub.3. The expression of adenosine receptor subtypes differs from tissue to tissue, and adenosine is thereby able to modulate a variety of physiological effects in a tissue-specific manner. The four known adenosine receptor subtypes interact with GTP-binding proteins (G-proteins) to mediate their effects. Each of the subtypes interacts with a distinct set of G-proteins, and differs in its affinity for different adenosine receptor agonists and antagonists. In addition, a compound can be an agonist or antagonist for more than one of the receptor subtypes; for example, some compounds such as caffeine and theophylline antagonize all four subtypes. The A.sub.1 and A.sub.3 adenosine receptors have been shown to interact primarily with inhibitory G-proteins (G.sub.i), which act to inhibit adenylate cyclase and reduce intracellular CAMP. The A.sub.2A receptor has been shown to elicit an opposite effect, acting through stimulatory G-proteins (G.sub.s), to increase adenylate cyclase activity and increase CAMP. The A.sub.2B adenosine receptor is believed to signal similarly through G.sub.s (like the A.sub.2A receptor), but may also signal through another class of G-proteins (G.sub.q) to increase phospholipase C activity, and subsequently, protein kinase C activity. Protein kinase C influences cell metabolism by phosphorylating enzymes and other cell proteins.
Numerous compounds have been reported as functioning as adenosine receptor antagonists; numerous uses for these compounds have also been reported. For example, U.S. Pat. Nos. 5,446,046, 5,631,260 and 5,668,139 disclose adenosine and/or xanthine derivatives that function in either the agonism or antagonism of A.sub.1 receptors. Use of these compounds to modulate the biological activity of adenosine through the A.sub.1 receptor, particularly in the treatment of cardiac arrhythmias, is also disclosed.
Xu et al., reported the use of a xanthine derivative, particularly 1,3-dipropyl-8-(p-acrylic)-phenylxanthine, as an A.sub.1 adenosine receptor antagonist that improves glucose tolerance in Zucker rats. American Journal of Physiology, 24:E271-E279 (1998).
Because of the potentially significant health risks associated with decreased insulin sensitivity which accompanies NIDDM, there remains a need for improved methods for increasing insulin sensitivity in patients with this and related diseases.